Matrix metalloproteinase­1 and microRNA­486­5p in urinary exosomes can be used to detect early lung cancer: A preliminary report.

The present study describes a novel molecular-genetic method suitable for lung cancer (LC) screening in the work-place and at community health centers. Using urinary-isolated exosomes from 35 patients with LC and 40 healthy volunteers, the expression ratio of MMP-1/CD63, and the relative expression levels of both microRNA (miRNA)-21 and miRNA-486-5p were measured. MMP-1/CD63 expression ratio was significantly higher in patients with LC than in the healthy controls {1.342 [95% confidence interval (CI): 0.890-1.974] vs. 0.600 (0.490-0.900); P<0.0001}. The relative expression of miRNA-486-5p in male healthy controls was significantly different from that in female healthy controls, whereas there was no significant difference in miRNA-21. Receiver operating characteristic curve (ROC) analysis of MMP-1/CD63 showed 92.5% sensitivity and 54.3% specificity, whereas miRNA-486-5p showed 85% sensitivity and 70.8% specificity for men, and 70.0% sensitivity and 72.7% specificity for women. The logistic regression model used to evaluate the association of LC with the combination of MMP-1/CD63 and miRNA-486-5p revealed that the area under the ROC curve was 0.954 (95% CI: 0.908-1.000), and the model had 89% sensitivity and 88% specificity after adjusting for age, sex and smoking status. These data suggested that the combined analysis of MMP-1/CD63 and miRNA-486-5p in urinary exosomes may be used to detect patients with early-stage LC in the work-place and at community health centers, although confirmational studies are warranted.

Interstitial pneumonia with autoimmune features that met the proposed diagnostic criteria for IgG4-related respiratory disease.

We held a multidisciplinary discussion (MDD) about a 61-year-old woman who had an interstitial lung disease (ILD) without extrathoracic lesions that met the classification criteria for interstitial pneumonia with autoimmune features (IPAF) and the proposed diagnostic criteria for immunoglobulin G4 (IgG4)-related respiratory disease (IgG4-RRD). Clinically, the marked progression of lung-limited diffuse lesions was consistent with IPAF. Serum IgG4 and rheumatoid factor levels simultaneously increased and did not contribute to a diagnosis. Pathologically, the significant hyperplasia of lymphoid follicles was consistent with rheumatoid arthritis (RA)-associated ILD. Pulmonary venous occlusions by intimal fibrosis and intimal thickening were not important because these occlusions are found in IgG4-related lung disease (IgG4-RLD) and also in IPAF or ILDs related to connective tissue diseases (CTDs). Radiologically, fibrosing shadows that remained in the lung periphery after treatment were compatible with RA-associated chronic ILD. We concluded that the present case was IPAF that met the proposed diagnostic criteria for IgG4-RRD.

Novel breast cancer screening: combined expression of miR-21 and MMP-1 in urinary exosomes detects 95% of breast cancer without metastasis.

Serum and tissue miR-21 expression in patients with breast cancer (BC) is a useful biomarker for cancer diagnosis, progression, and treatment. Matrix metalloproteinase-1 (MMP-1) is also important in breast cancer carcinogenesis. However, miR-21 and MMP-1/CD63 in urine exosomes in these patients have not been examined. Urine samples were collected from patients with BC and 26 healthy females. Urinary exosomes were isolated and confirmed by western blotting with anti-CD63 antibody and electron microscopy observation. MiR-21 and MMP-1/CD63 expression was examined by quantitative RT-PCR and western blotting, respectively. Patients with very early stage breast cancer were evaluated. MiR-21 expression in the patients was 0.26 [95% CI: 0.20-0.78], which was significant lower than in the 26 controls (1.00 [95% CI: 1.01-3.37], p = 0.0947). MMP-1/CD63 expression in patients was significantly higher than in controls (1.74 [95% CI: 0.86-5.08] vs 0.535 [95% CI: -0.01-2.81], p = 0.0001). Sensitivity and specificity were 0.708 and 0.783 for miR-21 and 0.792 and 0.840 for MMP-1/CD63, respectively. Sensitivity and specificity of combined expression were 95% and 79%, respectively. The sensitivity of MMP-1/CD63 expression in urinary exosomes was better than that of miR-21 expression. Thus, miR-21 and MMP/CD63 may be useful markers for BC screening.

Composite resection of the left upper lobe and superior segment (S6) of the lower lobe for lung cancer with a mediastinal lingular and basal pulmonary artery.

BACKGROUND: Preoperative evaluation and awareness of anatomical variations in the pulmonary vessel is essential for a secure pulmonary resection. We herein present a patient who underwent complex pulmonary resection for lung cancer with a mediastinal lingular and basal pulmonary artery that had been detected by preoperative three-dimensional computed tomography. CASE PRESENTATION: The patient was an asymptomatic 66-year-old woman who had a 39-pack-year smoking habit. Chest computed tomography (CT) revealed the tumor invading the left upper bronchus and pulmonary artery branches in the left upper lung lobe. Enhanced CT and three-dimensional (3D) images of the pulmonary artery revealed that pulmonary artery branches (A4 + 5, A8, and A9 + 10) were extending into the lingular and basal segment in ventral side of the left upper bronchus. We completed the resection by means of a composite resection of the left upper lobe and the superior segment of the lower lobe, avoiding pulmonary angioplasty to preserve the left lower lobe or pneumonectomy. CONCLUSIONS: 3D-CT is useful for detecting this rare variation of the left pulmonary artery before operation, allowing for proper resection.

Lung Adenocarcinoma in Never Smokers: Problems of Primary Prevention from Aspects of Susceptible Genes and Carcinogens.

Global statistics estimate that approximately 25% of patients with lung cancer are never smokers. We suggest that genes related to susceptibility to metabolic syndrome were present among those related to susceptibility to lung adenocarcinoma (AC) in never smokers. There are many questions concerning lung AC in never smokers, which is increasing in incidence, with female predominance, good prognosis, unique genes related to susceptibility and good response to treatment with specific agents. The purpose of this review was to investigate the carcinogenesis of lung AC in never smokers focusing on genes related to susceptibility to lung AC and carcinogens, including environmental factors. In order to clarify the carcinogenesis of lung AC in never smokers, the definition of never smokers, survey of environmental tobacco smoke, the presence of the physical characteristics of metabolic syndrome, and other carcinogens should be investigated for primary prevention of lung AC.

Genes associated with succeptibility to lung adenocarcinoma among never smokers suggest the mechanism of disease.

Global statistics estimate that 15% of all cases of lung cancer in men and 53% in women are not attributable to smoking, and these data indicate that worldwide, approximately 25% of patients with lung cancer are never smokers. The etiology of lung cancer is disputed. The present study reviews the genes associated with susceptibility to lung cancer among never smokers and suggests possibilities for the involvement of metabolic syndrome. The environment appears to have changed the genes susceptible to lung cancer. Classical genes associated with lung cancer are decreasing and novel emerging genes may reflect changes in lifestyle. We provide evidence that the genes associated with susceptibility to lung cancer in never smokers are very similar to those reported in patients with metabolic syndrome, and that simply quitting smoking is not sufficient as the primary means of preventing lung cancer.

Successful erlotinib rechallenge after both gefitinib- and erlotinib-induced interstitial lung diseases.

Epidermal growth factor receptor tyrosine kinase inhibitors, gefitnib and erlotinib, are effective for advanced nonsmall-cell lung cancer with epidermal growth factor receptor gene mutation. However, interstitial lung disease induced by these drugs is sometimes fatal, and discontinuation of the medication is the principle approach once this occurs. There are, however, some reports of cases in which rechallenge of gefitinib or erlotinib was successful, and it remains unclear when or how rechallenge should be attempted. We report the first successful case of erlotinib rechallenge after both gefitinib- and erlotinib-induced interstitial lung diseases. Our case suggests that, in interstitial lung disease induced by an epidermal growth factor receptor tyrosine kinase inhibitor, rechallenge with concurrent glucocorticoid administration and gradual increase of dosage could be a clinical option if imaging does not show a diffuse alveolar damage pattern, and if no alternative therapy is available.

Significant correlation between endothelial nitric oxide synthase (eNOS) expression and alveolar repair in elastase-induced rat pulmonary emphysema.

BACKGROUND AND PURPOSE: Angiogenic factors, such as endothelial nitric oxide synthase (eNOS), are thought to play an important role in the repair of pulmonary emphysema (PE); yet, the correlation of the factors involved has not been investigated. We conducted this study to clarify the positive correlation between eNOS expression and alveolar repair in PE recovery. METHODS: We used elastase to induce PE in rats, which were divided into Groups A (Control), B (G-CSF), C (PE) and D (PE + G-CSF). G-CSF was injected for 12 days, 4 weeks after which the alveolar walls, arterioles, and angiogenic factors including eNOS were examined histopathologically and by western blotting. RESULTS: In comparing Groups A, B, C, and D, the alveolar density was 2.4 ± 0.2, 2.4 ± 0.1, 1.8 ± 0.1, 2.5 ± 0.1 per 100 µm(2), respectively (C vs. others; p < 0.00001) and the number of arterioles was 4.5 ± 1.0, 5.6 ± 0.6, 3.2 ± 0.5, 5.5 ± 0.7/mm(2), respectively (C vs. others; p < 0.05). Immunohistochemical staining (IHC) revealed different eNOS expression in Group D versus Group C (p < 0.0001) and western blotting revealed different eNOS, VEGF, and FLT-1 expression in Group D versus Group C (p < 0.01, p < 0.05, p < 0.001), reflecting the contribution of angiogenesis to PE repair. eNOS showed a significantly positive correlation to alveolar density and arteriole repair. CONCLUSION: Alveolar repair was correlated positively with eNOS expression by vascular regeneration in elastase-induced rat PE.

A population-based study of gefitinib in patients with postoperative recurrent non-small cell lung cancer.

There is no standard treatment and there are no clearly defined guidelines for the treatment of postoperative recurrent non-small-cell lung cancer (NSCLC). We performed a retrospective population-based study to assess the benefits of treatment with gefitinib in patients with a postoperative recurrence of NSCLC in general clinical practice. This retrospective population-based study was conducted on patients with postoperative recurrent NSCLC who had been treated with gefitinib at 14 institutions in Ibaraki Prefecture between July 2002 and September 2007. The objective response rate to gefitinib therapy was 37.6% for local and distant recurrence. The median survival time following the start of gefitinib therapy was 12 months, and the one-year and two-year survival rates were 48.9 and 28.9%, respectively. The median survival time of the females was 19 months, and the median survival time of the males was 9 months (p=0.002). Univariate analysis showed that female gender, adenocarcinoma, a performance status (PS) of 0-1 and absence of smoking history were favorable prognostic factors. Only female gender and a PS of 0-1 were independent statistically significant prognostic factors in the multivariate analysis. The rate of greater than grade 1 interstitial lung damage as an adverse event was 3.5%. Gefitinib is a feasible treatment for postoperative recurrent NSCLC in general clinical practice, and a good response and prolonged survival were obtained, similar to the findings reported in published clinical studies that were conducted on highly selected patients.

[Clinicopathological study of small lung cancer (diameter of 2 cm or less) by uptake value of 18F-fluorodeoxyglucose].

18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for lung cancer may be a biomarker for malignancy as well as a useful tool for detection of nodal involvement and distant metastasis. The goal of this study was to clarify a relationship between clinicopathological findings and maximum standardized uptake value( SUVmax) obtained by preoperative PET in patients with non-small cell lung cancer in diameter of 2 cm or less. Between January 2008 and April 2011, 124 patients( 54 men and 70 women) with non-small cell lung cancer in diameter of 2 cm or less undergoing lobectomy or segmentectomy were enrolled. The relationship between SUVmax and clinicopathological findings as tumor diameter, histological type, pleural invasion, vascular invasion, lymphatic permeation and nodal involvement were analyzed. Correlation between SUVmax and findings such as vascular invasion and lymphatic permeation showed relatively strong in the patients with adenocarcinoma, on the contrary to the correlation in the patients with non-adenocarcinoma. No tumor showing SUVmax of 2 or less showed vascular invasion and/or lymphatic permeation as well as nodal involvement in any patients with adenocarcinoma. SUVmax of the primary tumor in diameter of 2 cm or less, can be a useful biomarker which indicates a surgical candidate for sublobar pulmonary resection as well as mediastinal nodal dissection, especially in patients with adenocarcinoma.

[Stump consolidation after video-assisted thoracoscopic segmentectomy].

Pulmonary segmentectomy by video-assisted thoracic surgery (VATS) is used for minimally invasive surgery for removal of small lung neoplasms, and stump consolidation is one of the potential postoperative complications. The objective of the present study is to clarify the incidence of stump consolidation and its predictive factors by assessing patients who underwent VATS segmentectomy in our department. Stump consolidation was defined as atelectatic lesions along the surgical stump with >10 mm thickness in horizontal sectional view by computed tomography, at least 3 months after surgery. Between February 2007 and September 2010, 70 patients (38 men and 32 women) with primary lung cancer (43 patients) and metastatic pulmonary tumor (27 patients) underwent VATS segmentectomy. Stump consolidations were seen in 7 patients. Univariate analysis showed the significant difference for the period of performed operation. Left-sided operation, especially segmentectomy of left S(1+2), was another predictive factor, though not significant. Stump consolidation after VATS segmentectomy can be deueloped by conbined workspace for stapling and misidentification of intersegmental plane. When division of the intersegmental plane is difficult, open thoracotomy should be undertaken to prevent such compliance.

Dual-phase FDG-PET imaging shows suspected malignancy that histological examination later confirmed as sclerosing mediastinitis: report of a case.

Sclerosing mediastinitis is a rare, benign disorder that is often indistinguishable from malignancy by conventional imaging techniques. The value of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the diagnosis of this disorder has not been elucidated. Recently, a few studies have reported the use of dual-phase FDG-PET imaging in the diagnosis of malignancies. The dual phase contains early- and late- phase images. The maximum standard uptake value (SUVmax) of late phase images of malignant lesions tends to be higher than those of early phase images. The present case showed that early-phase SUVmax was 5.93, and late phase, 8.92. We strongly suspected malignancy from the results of this new imaging technique, though the histological examination of the surgical samples provided the definitive diagnosis of sclerosing mediastinitis, Flieder stage II. This report describes the uncommon use of dual-phase FDG-PET computed tomography in the preliminary diagnosis of sclerosing mediastinitis. It is thought that current imaging studies are insufficient for the diagnosis of sclerosing mediastinitis, and the rarity of this disorder may prevent the development of imaging techniques. Histological confirmation is still essential for the definitive diagnosis of this disorder.

Proton beam therapy of Stage II and III non-small-cell lung cancer.

PURPOSE: The present retrospective study assessed the role of proton beam therapy (PBT) in the treatment of patients with Stage II or III non-small-cell lung cancer who were inoperable or ineligible for chemotherapy because of co-existing disease or refusal. PATIENTS AND METHODS: Between November 2001 and July 2008, PBT was given to 35 patients (5 patients with Stage II, 12 with Stage IIIA, and 18 with Stage IIIB) whose median age was 70.3 years (range, 47.4-85.4). The median proton dose given was 78.3 Gy (range, 67.1-91.3) (relative biologic effectiveness). RESULTS: Local progression-free survival for Stage II-III patients was 93.3% at 1 year and 65.9% at 2 years during a median observation period of 16.9 months. Four patients (11.4%) developed local recurrence, 13 (37.1%) developed regional recurrence, and 7 (20.0%) developed distant metastases. The progression-free survival rate for Stage II-III patients was 59.6% at 1 year and 29.2% at 2 years. The overall survival rate of Stage II-III patients was 81.8% at 1 year and 58.9% at 2 years. Grade 3 or greater toxicity was not observed. A total of 15 patients (42.9%) developed Grade 1 and 6 (17.1%) Grade 2 toxicity. CONCLUSION: PBT for Stage II-III non-small-cell lung cancer without chemotherapy resulted in good local control and low toxicity. PBT has a definite role in the treatment of patients with Stage II-III non-small-cell lung cancer who are unsuitable for surgery or chemotherapy.

Malignant pleural mesothelioma detected by spontaneous pneumothorax.

We report a middle-aged man, without occupational or environmental exposure to asbestos, who presented with spontaneous pneumothorax. Computed tomography showed a 13-mm right apical mass. He underwent tumorectomy and was diagnosed with malignant pleural mesothelioma. A local recurrence with multiple and diffuse pleural involvement later appeared. The patient eventually underwent panpleuropneumonectomy, recovered well, and has been doing well for 18 months.

Postoperative follow-up for patients with non-small cell lung cancer.

BACKGROUND: It is unclear whether postoperative follow-up by thoracic surgeons or chest physicians for non-small cell lung cancer (NSCLC) alters survival. PATIENTS AND METHODS: The charts of 1,398 NSCLC patients, diagnosed between 1980 and 2008, were reviewed. Prognostic factors contained therein were evaluated using univariate and multivariate analyses. Patients were divided into 2 groups according to the doctor in charge of their postoperative follow-up: the thoracic surgeon group and the chest physician group. The doctors in charge of following up the patients were also analyzed for prognostic significance. RESULTS: In the univariate and multivariate analyses, age 65 years or younger, female sex, early pathological stage, Charlson Index score of 0-1, absence of adjuvant therapy, and follow-up by a chest physician were significantly favorable prognostic factors. Examined overall, NSCLC patients in the chest physician group had longer survival than those in the thoracic surgeon group. The difference in survival of patients with advanced disease was also statistically significant between these 2 groups. CONCLUSIONS: Our results indicate that early detection of asymptomatic disease by regular follow-up including chest computed tomography scan may improve the chance of treatment with curative intent and thus may increase survival, irrespective of the doctor in charge of follow-up.

Proton beam therapy for patients with medically inoperable stage I non-small-cell lung cancer at the university of tsukuba.

PURPOSE: To evaluate in a retrospective review the role of proton beam therapy for patients with medically inoperable Stage I non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From November 2001 to July 2008, 55 medically inoperable patients with Stage I NSCLC were treated with proton beam therapy. A total of 58 (T1/T2, 30/28) tumors were treated. The median age of study participants was 77 years (range, 52-86 years). A total dose of 66 GyE in 10 fractions was given to peripherally located tumors and 72.6 GyE in 22 fractions to centrally located tumors. RESULTS: The rates (95% confidence interval) of overall and progression-free survival of all patients and of local control of all tumors at 2 years were 97.8% (93.6-102.0%), 88.7% (77.9-99.5%), and 97.0% (91.1-102.8%), respectively. There was no statistically significant difference in progression-free rate between T1 and T2 tumors (p = 0.87). Two patients (3.6%) had deterioration in pulmonary function, and 2 patients (3.6%) had Grade 3 pneumonitis. CONCLUSION: Proton beam therapy was effective and well tolerated in medically inoperable patients with Stage I NSCLC.

Limited thymectomy for stage I or II thymomas.

BACKGROUND: Once an anterior mediastinal tumor has been diagnosed as a thymoma, complete excision including the thymic gland and perithymic fat is currently the procedure of choice. However, little is known about the clinical outcome of grossly encapsulated thymomas excised only with the surrounding tissue while leaving a part of the thymic gland. METHODS: A retrospective historical comparative study was conducted on 79 patients who had received surgery for stage I (n=25) or stage II (n=54) thymomas. Total thymectomy was performed in 61 patients (Total Thymectomy Group), whereas resection of tumors with only the surrounding tissue was carried out in 18 (Limited Thymectomy Group). The follow-up interval was longer in the Limited Thymectomy Group because these patients were treated longer ago (104.2+/-58.1 months vs 67.3+/-54.8 months, p<0.05). RESULTS: One case in the Limited Thymectomy Group showed postoperative myasthenia gravis (5.6%). Two patients with multiple thymomas (2.5%) were treated with total thymectomy. One case in the Limited Thymectomy Group, which had been diagnosed as Masaoka stage II and WHO type B3 at initial surgery, recurred. None died of tumor progression in this study. Disease free survival rates at 10 years did not differ between the Limited Thymectomy and Total Thymectomy Groups (85.7% and 82.0%, respectively). There were no statistical differences in the incidence of postoperative myasthenia gravis and disease free survival between the two groups. CONCLUSION: Resection of thymomas with surrounding tissue instead of total thymectomy can be indicated for stage I or II thymomas in light of disease free and overall survival, post-operative onset of MG, and the incidence of multiple lesions.

Increased cytoplasmic S100A6 expression is associated with pulmonary adenocarcinoma progression.

S100A6 is a calcium-binding protein implicated in many cellular processes and frequently upregulated in cancer. Recently it was reported that S100A6 is one of the genes having higher expression in adenocarcinoma mixed subtype with a bronchioloalveolar carcinoma (BAC) component than in pure BAC. To clarify the association of S100A6 expression with stepwise progression of lung adenocarcinoma, S100A6 protein expression was examined on immunohistochemistry in 92 formalin-fixed and paraffin-embedded lung adenocarcinomas. Both the nucleus and cytoplasm of the tumor cells were stained, and the nuclear and cytoplasmic expression of S100A6 was assessed individually. In addition, six frozen surgical specimens were selected, and the expression of S100A6 was confirmed on western blotting. As a result, although it was not possible to detect any significant correlation between nuclear S100A6 immunoreactivity and tumor progression, advanced adenocarcinoma had significantly higher cytoplasmic S100A6 expression than non-invasive lesions or normal lung tissue (P < 0.05). Moreover, the BAC component tended to have weaker staining than any of the other components. These findings indicate that S100A6 may be associated with the stepwise progression and/or invasion of lung adenocarcinoma, especially BAC-type adenocarcinoma. The present results suggest the utility of S100A6 immunohistochemistry as a marker for estimation of malignancy in adenocarcinoma with a BAC component.

Increased fluorodeoxyglucose-uptake in positron emission tomography with an endobronchial schwannoma occluding the left main stem bronchus.

A 48-year-old woman suffering from left-side back pain and a 3-year history of coughing was found to have a submucosal lesion occluding the left main bronchus by chest computed tomographic scanning and bronchoscopy. The lesion showed a high standardized uptake value of 3.9 in positron emission tomography with fluorine-18 labeled fluorodeoxyglucose scanning (FDG-PET). The tumor was resected with the posterior wall of the left main bronchus through a postrolateral thoracotomy, and a large defect in the membranous portion was reconstructed in the manner of wedge bronchoplasty, preserving the lung parenchyma. Pathological findings confirmed the diagnosis of schwannoma with no malignant cells. Schwannoma should be included in the differential diagnosis of endobronchial tumors with high standardized uptake values in FDG-PET.

Blood flow velocity is reduced in a tumor micro-dissemination in the visceral pleura in anesthetized open-chest rat lung.

BACKGROUND: Recently we developed a method to observe pulmonary micrometastasis by labeling cancer cells with green fluorescent protein (GFP). We applied the method for observation of micro-dissemination on the visceral pleura. MATERIALS AND METHODS: RCN9 rat colon cancer cells labeled with GFP were injected into the pleural cavity of Fischer F344 rats. Six weeks after injection, the chest wall was resected under general anesthesia and the lung surface was observed by real-time confocal laser-scanning microscopy. Blood flow was visualized by intravenous injection of fluorescein isothiocyanate-labeled red blood cells, by which blood flow velocity was measured. RESULTS: Dissemination was created in 4 out of 5 rats. Fifteen sites of micro-dissemination were observed (mean diameter, 35.8+/-13.3 microm). Blood flow velocity was 114.1+/-26.1 microm/s in the tumor tissue and 183.4+/-35.0 microm/s out of the tumor tissue. CONCLUSION: We were able to observe pleural micro-dissemination. Blood flow velocity was significantly lower in the tumor tissue.